Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ileal fatty acid binding protein (FABP6) is known to be involved in enterohepatic bile acid metabolism. We have previously found a significant association between the rare allele of the FABP6 Thr79Met polymorphism and lower type 2 diabetes risk in a small case-control study (192 cases and 384 controls) embedded in the large EPIC-Potsdam cohort. A priori functional implication of the amino acid change was gained from in-silico analysis. In this study, we analysed an independent nested case-cohort including 543 incident type 2 diabetes cases from the EPIC-Potsdam cohort and a case-control study including 939 type 2 diabetes cases from KORA to confirm the association with type 2 diabetes and performed association analyses with quantitative disease-related measures in 2112 non-diabetic individuals. Homozygosity for the Met-allele was associated with lower risk of type 2 diabetes (EPIC-Potsdam: 0.70, P=0.04; KORA: 0.79, P=0.06) if adjusted for age, sex, body mass index (BMI), and waist circumference. The homozygous rare variant showed a significant interaction (P=0.006) with BMI. Relative risks in different categories (BMI <25, 25-30, and >30 kg/m(2)) showed an association exclusively in obese (BMI >30 kg/m(2)) individuals (combined risk ratio: 0.62, 95% CI 0.45-0.86). In non-diabetic individuals from the general adult population, no significant associations were observed with plasma total cholesterol, LDL-, and HDL-cholesterol, triglyceride, insulin and glucose concentration. In summary, we found evidence that the-putative functional-Thr79Met substitution of FABP6 confers a protective effect on type 2 diabetes in obese individuals.
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PMID:Evidence for the Thr79Met polymorphism of the ileal fatty acid binding protein (FABP6) to be associated with type 2 diabetes in obese individuals. 1974 71

Visfatin, ghrelin, and apelin are the most recently identified adipocytokines; but their response to insulin-sensitizing agents is poorly clarified. We aimed to assess the differential effects of either rosiglitazone or metformin monotherapy on the aforementioned adipocytokines in patients with type 2 diabetes mellitus (T2DM). One hundred T2DM patients (30 men, 70 women), with poor glycemic control (glycosylated hemoglobin >6.5%) while taking 850 mg of metformin daily, were enrolled. All participants were randomized to receive either adjunctive therapy with rosiglitazone (8 mg/d, n = 50) or the maximum dose (2550 mg/d) of metformin (MET group, n = 50). Anthropometric parameters, glycemic and lipid profile, high-sensitivity CRP (hs-CRP), insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), visfatin, ghrelin, and apelin were assessed at baseline and after 14 weeks of therapy. Both rosiglitazone and metformin led to similar, significant improvement in glycemic profile and apelin levels, whereas lipid parameters, fat mass, and visfatin remained almost unaffected (P > .05). Insulin resistance was significantly attenuated in both groups, but to a lesser degree in the MET group (P = .045). Rosiglitazone-treated patients experienced a significant decrease in hs-CRP and systolic blood pressure compared with baseline values and those of the MET group (P < .05). Besides, rosiglitazone treatment considerably increased plasma ghrelin (3.74 +/- 1.52 ng/mL) in comparison with either baseline (P = .034) or metformin monotherapy values (-2.23 +/- 1.87 ng/mL, P = .008). On the other hand, the MET group, rather than the rosiglitazone group, had decreased body mass index (-0.79 +/- 0.47 vs 0.56 kg/m(2), P = .009). The aforementioned changes in apelin and ghrelin were independently associated with HOMA-IR changes. Both rosiglitazone and metformin favorably changed glycemic indexes and apelin levels. The addition of rosiglitazone seemed to confer greater benefits in ghrelin, hs-CRP, systolic blood pressure, and HOMA-IR regulation than metformin monotherapy. Although these results reflect improvement in cardiovascular risk profile, the overall clinical importance of insulin sensitizers must be further assessed.
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PMID:Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus. 1981 43

Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1alpha, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.
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PMID:Caloric restriction: from soup to nuts. 1985 62

Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich Gck(M210R) mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While beta-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and beta-cell volumes and the total volume of isolated beta-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and beta-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total beta-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of beta-cell mass and its relevance in MODY 2 patients.
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PMID:Phenotypic and pathomorphological characteristics of a novel mutant mouse model for maturity-onset diabetes of the young type 2 (MODY 2). 1995 46

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects (n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2-3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% Vo(2peak) (MET + Ex). A second group (n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex (group 1), or immediately after Ex (group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU.m(2).min(-1)) clamp enriched with [6,6-(2)H]glucose. Insulin sensitivity was 54% higher after Ex (P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKalpha2 activity was elevated threefold (P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.
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PMID:Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals. 2007 60

Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNA(Leu(UUR)) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNA(Leu(UUR)). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders.
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PMID:Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. 2884 73

The objective of the present study was to examine the effect of acute, methionine-induced hyperhomocysteinemia (HHCY) on endothelial function and indices of arterial stiffness in subjects with type 2 diabetes mellitus (T2DM). A total of 30 subjects with T2DM, free of macrovascular disease were examined in a crossover study. L-methionine (M) (0.1 g/kg) and water (W) load were given in random order with an interval of about 1 week in between. Endothelial function was assessed by flow-mediated vasodilation (FMD). Arterial stiffness was assessed by determination of augmentation index (AI). Measurements were performed in the fasting state, 1, 2 and 3 h after the M or the W load. Total plasma homocysteine (HCY) levels did not change after W administration, while M administration resulted in a significant increase in HCY concentrations at 3 h. FMD throughout the experiment expressed as area under the curve (AUC) was significantly lower after the M than after the W load. Consistent with impairment in endothelial function, the AUC of AI was significantly higher after the M than after the W administration. Acute HHCY impairs endothelial function and increases arterial stiffness in patients with T2DM. This effect is probably mediated by a reduction of nitric oxide bioavailability in endothelium.
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PMID:Acute hyperhomocysteinemia impairs endothelium function in subjects with type 2 diabetes mellitus. 2020 Aug 16

The aim of this study was to investigate the effects of acute, methionine-induced hyperhomocysteinaemia on endothelial function of skin microcirculation in diabetic compared with non-diabetic persons. Endothelial- and non-endothelial-dependent vasodilatation of the skin microcirculation were evaluated in 20 persons with type 2 diabetes (59.95+/-2.36 years old) and 24 age- and gender-matched controls using laser Doppler flowmetry, during fasting and four hours after 0.1 g/kg methionine-induced acute hyperhomocysteinaemia. Methionine loading caused a comparable increase of homocysteine in the two groups. Four hours after induction of acute hyperhomocysteinaemia, endothelial-dependent vasodilatation (acetylcholine effect) was lower in the diabetic patients compared with the controls ([mean+/-SEM] 8.09+/-1.18-fold increase in diabetic patients vs. 11.11+/-1.33-fold increase in controls, p=0.027). The same was observed for the endothelial-independent vasodilatation (sodium-nitroprusside effect, 7.55+/-0.80-fold increase in the diabetic patients vs. 12.19+/-1.26-fold increase in controls, p=0.008). Acute hyperhomocysteinaemia causes a decreased response of both endothelial-dependent and endothelial-independent vasodilatation of the skin microcirculation in diabetic compared with non-diabetic persons. These alterations might contribute to the vascular complications of hyperhomocysteinaemia in diabetes, and especially the microvascular ones.
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PMID:Acute hyperhomocysteinaemia blunts endothelial dependent and endothelial independent vasodilatation in diabetic patients. 2047 1

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.
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PMID:Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. 2080 51

Although insulin resistance in T2DM (type 2 diabetes mellitus) is usually referred to glucose and lipid metabolism, the question whether such a resistance affects also amino acid and protein metabolism is both relevant and not easy to be answered. Available data indicate a reduced response to insulin in the inhibition of proteolysis at low, near basal hormone levels, whereas such a response appears to be normal at high physiological doses. In most studies in T2DM subjects the stimulation of whole-body protein synthesis in the presence of hyperinsulinemia and euaminoacidemia appears to be normal, although one single study reported lower rates in male T2DM subjects with obesity. The response to insulin of plasma protein synthesis (albumin and fibrinogen) is also normal. However, some metabolic steps of amino acids related to vascular complications (methionine and arginine) exhibit a defective response to insulin in T2DM subjects with nephropathy. In summary, although gross alterations in the response of whole-body protein turnover are not evident in T2DM, specific investigations reveal subtle abnormalities in metabolic steps of selected amino acids. Furthermore, the effects of interaction between diabetes (with the associated insulin resistance) and older age in the pathogenesis of sarcopenia in the elderly deserve more specific studies.
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PMID:Insulin resistance of amino acid and protein metabolism in type 2 diabetes. 2149 74


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